Methods The ESPRIT BVS system is a device-drug combination consisting of an everolimus-eluting poly-l-lactide scaffold. Safety and performance were evaluated in 35 subjects with symptomatic claudication.

Results Lesions were located in the SFA (88.6%) and EIA (11.4%). Mean lesion length was 35.7 ± 16.0 mm. The study device was successfully deployed in 100% of cases, without recoil. Procedure-related minor complications were observed in 3 patients (groin hematoma, dissection). Within 2 years there was 1 unrelated death, but no patients in this cohort had an amputation. At 1 and 2 years, the binary restenosis rates were 12.1% and 16.1%, respectively, and target lesion revascularization was performed in 3 of 34 patients (8.8%) and 4 of 32 patients (11.8%), respectively. The ankle brachial index 0.75 ± 0.14 improved from pre-procedure to 0.96 ± 0.16 at 2 years’ follow-up. At 2 years, 71.0% of the patients were Rutherford-Becker 0, and 93.5% achieved a maximum walking distance of 1,500 feet.

Conclusions The safety of the ESPRIT BVS was demonstrated with no procedure or device-related deaths or amputations within 2 years. The low occurrence of revascularizations was consistent with duplex-ultrasonography showing sustained patency at 2-years. (A Clinical Evaluation of the Abbott Vascular ESPRIT BVS [Bioresorbable Vascular Scaffold] System [ESPRIT I]; NCT01468974)

A bioresorbable vascular scaffold (BVS) theoretically provides radial support in the acute procedural setting and during the healing phase to treat flow-limiting dissection, vascular recoil, and constrictive remodeling (1,2). The device should be resorbed once the acute processes have subsided. Due to its temporary nature, BVS will not incur the long-term limitations of metal stents such as continuous mechanical irritation of the vessel wall, device fracture, limitation of future options for endovascular or surgical revascularization, and artifact on noninvasive imaging such as those seen on computed tomography angiography (CTA) and on magnetic resonance angiography (MRA).

Various types of bioresorbable metallic or polymeric stents are currently under investigation (1–11). Today, those based on lactide–derived polymers are the most advanced because of their biocompatibility and their hydrolytic degradability. The drug-eluting coronary version of the fully resorbable, Absorb BVS (Abbott Vascular, Santa Clara, California), has been initially tested in humans in the Absorb trial cohort A, which demonstrated excellent long-term clinical results up to 5 years, with a major adverse cardiac event rate of only 3.4% (12). Absorb cohort B, a single-arm trial of 101 patients, demonstrated a sustained long-term patency to 3 years, comparable to that seen in metallic drug-eluting stents (DES), confirmed by angiography, intravascular ultrasonography (IVUS), and optical coherence tomography (OCT). It should be noted that drug elution is a critical component required to control neointimal proliferative reaction to procedural injury and scaffold implantation (7–11). The first studies of non–drug-eluting BVS in peripheral arteries showed high restenosis rates of up to 68% at 12 months (13,14).

The evaluation of safety and performance of the ESPRIT BVS system for treatment of subjects with symptomatic peripheral artery disease (PAD) is the focus of this first-in-human clinical investigation.

Methods

The ESPRIT I clinical investigation was a prospective, single-arm, open-label, multicenter trial in which 35 subjects were registered to receive the study device at 7 clinical sites. The protocol was developed and conducted in accordance with the International Conference on Harmonisation/Good Clinical Practice Guideline and the Declaration of Helsinki (ISO 14155-1 and ISO 14155-2). It was approved by the local ethics committees, and written informed consent was obtained from all patients. The study was registered at the ISRCTN Register (NCT01468974).

Investigational device

The ESPRIT BVS system (Abbott Vascular, Santa Clara, California) consists of a polymer backbone of poly-L lactide coated with a thin layer of a 1:1 mixture of poly-D, l-lactide polymer, and the anti-proliferative drug everolimus to form an amorphous drug-eluting coating matrix containing 100 μg of everolimus/cm2 of scaffold. The design consists of serpentine rings that open during balloon expansion. Each ring is connected to neighboring rings by connector links. Platinum markers on the proximal and distal ends of the scaffold provide visibility under fluoroscopy (Figure 1). The ESPRIT BVS has crush recovery properties which help withstand the mechanical forces inherent in the superficial femoral artery (SFA). The nominal length is 58 mm, and the nominal expanded diameter is 6 mm.

Study objective

The purpose of the ESPRIT I clinical study was to evaluate the safety and performance of the ESPRIT BVS in patients with intermittent claudication due to PAD of the SFA and external iliac artery (EIA).

Inclusion and exclusion criteria

Key inclusion criteria were patients with symptomatic claudication (RB 1 to 3) having a single de novo lesion of the SFA or iliac arteries, lesion length ≤50 mm, and vessel diameter from ≥5.0 mm to ≤6.5 mm. Key exclusion criteria were inability to walk, presence of ulcers on either foot, previous minor or major amputation of either lower extremity, occluded ipsilateral inflow artery, and a target lesion with severe calcification.

Treatment

All procedures were performed using percutaneous techniques under local anesthesia, with ipsilateral or contralateral access. Following mandatory pre-dilation of the target lesion, the ESPRIT BVS was deployed by balloon inflation up to 8 atm. A maximum of one 6.0mm × 58mm ESPRIT BVS study device was used to treat the target lesion. Acute success was defined as the achievement of successful delivery and deployment of the study device at the intended target lesion.

Adjuvant medical therapy

Unless the patient was receiving chronic antiplatelet medication, the patient was treated with a loading dose of clopidogrel bisulfate, 300 mg or prasugrel 60 mg, and aspirin, 300 mg. Unfractionated heparin or bivalirudin was used for procedural anticoagulation. Subjects who received the study device were maintained on a thienopyridine agent (e.g., 75 mg of clopidogrel bisulfate or 10 mg of prasugrel daily) for a minimum of 6 months following the procedure.

Substudies

A pharmacokinetic (PK) substudy was performed with assessments of everolimus plasma levels before scaffold placement at 1, 4, and 8 hours following device deployment, prior to discharge and at 1 month following the procedure. In addition an imaging substudy was performed to demonstrate the visibility during CTA and MRA.

Statistical analysis

Due to the small size of this feasibility study, there was no formal hypothesis testing. The sample size requirement was determined by assessing the minimal number of subjects required to provide reliable and nontrivial results and to achieve in the Kaplan-Meier estimates results with a standard error of <10%. Baseline demographics, clinical characteristics, and angiographic endpoints were analyzed in this intention-to-treat population, using descriptive statistics. For binary variables such as binary restenosis, TLR counts, percentages, and standard error using the Clopper-Pearson method was calculated. For continuous variables such as percent diameter stenosis, means, and standard deviations using the Gaussian approximation was calculated. If the assumption of normality seemed untenable, nonparametric summary statistics was presented instead. For time-to-event variables such as primary patency rate and freedom from TLR, survival curves were constructed using Kaplan-Meier estimates.

Results

Baseline demographics and risk factors are summarized in Table 1. Lesion characteristics are summarized in Table 2. The majority of lesions were located in the SFA (88.6% [n = 31 of 35]), followed by the EIA (11.4% [n = 4 of 35]). The lesion length as assessed by the angiographic core laboratory was 35.7 ± 16.0 mm. Prior to any treatment, the in-segment diameter stenosis (DS) in the vessel was 80.0 ± 15.1%. As assessed by the core laboratory, lesion calcification was absent or mild in 40% (n = 14 of 35), moderate in 40% (n = 14 of 35), and severe in 20% (n = 7 of 35). However, investigators did not report severe calcifications in any case.

Acute procedural success was achieved in 100% of cases (Figure 2). One patient withdrew in the first month the study was begun. There was 1 death due to an unrelated stroke in year 2, 1 myocardial infarction in a patient with known CAD in year 1, and no amputations. Procedure-related adverse events included 1 flow-limiting dissection (treated by bare metal stent implantation during the index procedure) and 2 groin hematomas, which resolved without intervention. A total of 34 patients were available for follow-up at 1 year (35 enrolled, 1 withdrew); a total of 32 patients were available for follow-up at 2 years (35 enrolled, 1 withdrew, 1 died, and 1 was lost to follow-up).

Duplex ultrasonography results are shown in Table 3. Mean PSVR was 1.27 ± 0.29 post-procedure, rose to 1.66 ± 1.16 at 1-year follow-up, and reached 1.56 ± 0.49 at 2-year follow-up. Cumulative distribution of evaluable PSVR at follow-up at 1 (n = 29) and 6 months (n = 30), then at 1 (n = 29) and 2 years (n = 24) can be found in Figure 3. At 1 and 6 months, all subjects had an evaluable PSVR <2.4, which as indicated on the plot, represents the transition point to binary restenosis. At 1 year there were 2 subjects with PSVR >2.4, while at 2-year there was 1 additional subject with PSVR >2.4. The distributions are similar across follow-up times and do not show separation over time that would suggest disease progression in the treated segments.

Four patients had TLR due to occlusion (n = 2) and stenosis (n = 2) within the study device, none at 6 months, 3 at 1 year and another 1 within the 2-year follow-up. Three TLR were clinically driven, 1 was performed during the 1-year required control angiogram in an asymptomatic patient. Freedom from TLR was 91.2% (SE ± 4.9% [n = 3 of 34]) and 88.2% (SE ± 5.5% [n = 4 of 31]) at 1 and 2 years of follow-up, respectively (Figure 4). CDUS demonstrated beginning degradation of the ESPRIT device at 2 years’ follow-up. Investigators have not reported embolization of BVS fragments during the 2-year follow-up.

The scaffold was radiolucent on CTA as expected; however, the platinum markers were clearly visible. The ESPRIT BVS did not cause any signal loss of the contrast-enhanced vessel lumen when imaged with MRI (Figure 2).

Angiographic results

By core laboratory assessment, the pre-procedure minimum lumen diameter (MLD) was mean 1.01 ± 0.78 mm, and the in-segment percent diameter stenosis (%DS) was mean 80.0 ± 15.1%. After implantation, in-scaffold MLD was mean 4.46 ± 0.72 mm and in-scaffold %DS was mean 9.2 ± 7.2%. Follow-up angiography at 1-year was obtained in 28 subjects (Figure 2). Core laboratory analysis of the images revealed 1 thrombotic device occlusion, and in-scaffold MLD was mean 3.24 ± 1.22 mm and in-scaffold %DS was mean 31.8 ± 26.1%. Further details of the angiographic results are shown in Table 4. The impact of vessel size on angiographic outcomes was explored in a post hoc subgroup analysis of the in-scaffold %DS post-procedure and at 1 year follow-up. For those patients who received 1 year angiographic follow-up with an evaluable segment maximum diameter (Dmax), in subjects with a Dmax less than median (n = 14) the post-procedure in-scaffold %DS was 8.9%, and in subjects with a Dmax greater than the median (n = 13), it was 8.5%. Post-procedure in-scaffold %DS was 8.7% in all subjects. At 1 year, the in-scaffold %DS was 31.8% in all subjects (a change of +23.1%). In patients with a Dmax equal to or less than the median, the in-scaffold %DS was 20.1% (a change of +11.2%), but in patients with a Dmax greater than the median, the in-scaffold %DS was 44.4% (a change of +35.9%) (p = 0.023). Thus, the vessel narrowing at 1 year was substantially lower in smaller vessels where the scaffold was oversized by 1 mm and imbedded deeply in the vessel wall. Consistent with the higher progression of angiographic restenosis in larger vessels, all 3 subjects having TLR at 1-year had Dmax values above the median.

Rutherford-Becker Clinical Category for All Patients Before and After Procedure and at 1-, 6-, 12-, and 24-Month Follow-Up Examinations

For the 3 subjects enrolled in the PK substudy, the everolimus blood concentrations were 14.6 to 15.6 ng/ml at 1-h post scaffold placement, 7.5 to 11.6 ng/ml at 4 h, 5.56 to 5.59 ng/ml at 8 hours, and 2.78 to 3.99 ng/ml at 1 day post-procedure. At 30 days, everolimus blood concentrations were below the lower limit of quantification (LLOQ) for all 3 subjects.

Discussion

The key findings of this first-in-humans clinical evaluation of ESPRIT BVS were: 1) the BVS was implanted successfully in all 35 patients, with residual %DS of <10% and no indication of acute recoil; 2) the ESPRIT BVS is safe as demonstrated by an absence of related deaths or amputations to 2 years; 3) sustained patency at 2 years with freedom from binary restenosis at 12-month and 24-month in 87.9% and 83.9%, respectively; 4) low occurrence of revascularizations (4 of 35 patients) and freedom from TLR at 12 and 24 months in 91.2% and 88.2%, respectively; 5) sustained improvement in Rutherford-Becker clinical category and walking distance was up to 24 months of follow-up. This demonstrated that, in symptomatic, short, mild-to-moderately calcified TASC (TransAtlantic Inter-Society Consensus) A lesions (15), the ESPRIT drug-eluting BVS did not cause safety concerns and 2-year patency rates were encouraging.

If we compare these results with those of other studies of patients with similar patterns of PAD (TASC A SFA lesion), the results of this study look promising. In the FAST (femoral artery stent) trial, lesions of similar length were treated by bare metal stents. The 1-year CDUS assessed freedom from binary restenosis rate was 68.3%, and the freedom from TLR rate was 85.1% (16). In the RESILIENT (A Randomized Study Comparing the Edwards Self-Expanding LifeStent vs. Angioplasty-alone In Lesions INvolving The SFA &/or Proximal Popliteal Artery) trial, TASC A and B SFA lesions were treated. The primary patency rate for the stent group was 81.3% at 1-year follow-up. Freedom from TLR was 87.3% at 1 year and 78.8% at 2 years (17,18). In the ZILVER PTX (paclitaxel-eluting ZILVER stent) trial lesions with a mean lesion length of 54 mm were treated. The 1-year primary patency rate for the DES cohort was 83.1%, and improvement in the RB clinical category was observed in 65.6%. Freedom from TLR in the randomized versus single arm study was 90.8% versus 89.3% at 1 year and 86.6% versus 80.5% at 2 years (19,20). Recently a number of randomized trials evaluating drug-eluting balloons were published. In the FemPac (Femoral Paclitaxel Randomized Pilot) trial, TASC A-B lesions (median length of 40 mm) were treated. At 6 months the binary restenosis rate was 19% (21). In the THUNDER (Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries) and LEVANT (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) I trials, TASC A-B lesions (mean length of 75 to 81 mm) were treated. The 1-year TLR rate was 10% in the THUNDER trial and 30% at 2 years in the LEVANT I trial (22,23). In the IN.PACT SFA (IN.PACT drug-eluting balloon in superficial femoral artery) trial (mean lesion length of 89 mm) the 1-year primary patency rate was 82.2%, in the LEVANT II trial (mean lesion length 62mm) the 1-year primary patency rate was 65.2% (24,25).

A late catch-up phenomenon after the first year that was observed with the everolimus eluting nitinol stent in the STRIDES (Superficial Femoral Artery Treatment with Drug-Eluting Stent) trial has not been observed in this trial (26,27). The maximum everolimus plasma concentration in ESPRIT-treated patients (14.6 to 15.6 ng/ml) was slightly higher than that achieved in patients treated with the slower-eluting STRIDES stent (4.66 ng/ml), similar to patients treated with chronic oral everolimus for immunosuppression (22 ng/ml) and far less than levels achieved through high-dose oncologic chemotherapy (174 ng/ml).

Study limitations

Limitations of the study are the small number of patients treated and that only patients with short not-severely calcified lesions were included. The scaffold needs to be tested in TASC B and C lesions as well and should be compared to other drug-eluting technologies.

Conclusions

This preliminary first-in-human trial of an everolimus-eluting BVS in patients with PAD demonstrated no safety concerns in this small sample and efficacy during 2 years of follow-up were encouraging. The 1-year and 2-year freedom from TLR seems comparable to results of drug-eluting balloons and drug-eluting metal stents for peripheral arteries.

Perspectives

WHAT IS KNOWN? Bioresorbable drug-eluting scaffolds have demonstrated excellent clinical results in coronary artery disease, comparable to those seen in metallic drug-eluting stents.

WHAT IS NEW? This is the first-in-human study of an everolimus-eluting BVS for treatment of symptomatic claudication. In comparison to non–drug-eluting BVS, a high 2-year patency rate and low 2-year TLR rate have been demonstrated.

WHAT IS NEXT? The BVS needs to be tested in TASC B-C lesions and should be compared to other drug-eluting technologies such as DES and DEB in patients with PAD.

Footnotes

The study was supported and monitored by Abbott Vascular. Drs. Lammer, Bosiers, Zeller, Scheinert, and Vermassen are members of Abbott Vascular scientific advisory board. Dr. Lammer received honorarium as principal investigator of the ESPRIT I study. Dr. Schmidt consults for Abbott Vascular. Dr. Popma has received grants from Abbott Vascular. Drs. McGreevy and Rapoza are employees of Abbott Vascular. Dr. Schwartz is a former employee of Abbott Vascular. Dr. Jaff is a uncompensated advisor to Abbott Vascular; a board member of VIVA Physicians; and an equity shareholder in PQ Bypass. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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